Pancreatic cancer accounts for approximately 2 to 3% of all malignant tumors. Every year, about 200,000 people around the world die from pancreatic cancer, and its death toll is the 5th largest in malignant tumors. In Japan, about 20,000 people die annually. Risk factors for pancreatic cancer development include diabetes, chronic pancreatitis, smoking, and the like, and family history has also been reported to be one of the risk factors. Various attempts of early diagnosis have been made, including improvement of diagnostic imaging; however, most of the patients are diagnosed at advanced stages when they show resistance to chemotherapy. Thus, their five-year survival rate is about 9.7%, and only about 13% even in surgically-removed cases. Pancreatic cancer results in the most unfavorable prognosis among digestive system cancers. Due to this difficulty in diagnosis, there is a gradual increase in the incidence of pancreatic cancer as a cause of cancer death, especially in developed countries. Although multidisciplinary treatments, primarily surgical resection, and other treatments such as radiotherapy and chemotherapy are being carried out, they have not dramatically improved therapeutic effects, and novel therapeutic strategies are urgently needed.
Cholangiocellular carcinoma accounts for about 10% of primary liver cancer, and is the second most common cancer, following hepatocellular carcinoma. It shows poor clinical characteristics, and in many cases, the cancer is detected at advanced stages accompanying lymph node metastasis, intrahepatic metastasis, and the like. The five-year survival rate is about 20%, and is 35% in surgically-removed cases, but is very poor, only 7.4%, in surgically unremoved cases. Although surgical resection is the only therapy that can be expected to lead to long-term survival, many patients are already inoperable at the time of detection (rate of surgery: 66%, noncurative resection rate: 20%). Both anticancer drug sensitivity and radiosensitivity of patients are low, and the establishment of a therapy for inoperable cases, including noncurative resection cases, has been desired.
Compared to Western countries, morbidity rate of gastric cancer is high in Asian nations, such as Japan and China. Early detection of gastric cancer has become possible by the spread of medical tests, and progress of digestive endoscopic instruments and inspection techniques, hence decreasing the number of patients. However, gastric cancer is still the second leading cause of death in malignant neoplasms among Japanese, and its rate in cause of death is still high. Colon cancer is the second most common cancer in Western countries, and is the third most common cause of death in malignant neoplasms in Japan. Gastric cancer and colon cancer are treated mainly by surgical resection, and also by chemotherapy, radiotherapy, and the like. Immunotherapy that suppresses cancer growth by improving the immunity of the cancer patient against the cancer is attracting attention as a novel therapy for metastatic cancer and intractable cancer, against which, application of the previously mentioned therapies is impossible.
Lung cancer is continuously increasing in recent years around the world, and currently, about one million people die of lung cancer in a year. Lung cancer death is continuously increasing also in Japan and is thought to reach 123,000 in 2015. It is the leading cause of death in malignant neoplasms in Japan. The number of patients is thought to increase as the aging of the population progresses. Early detection and early treatment are important in lung cancer treatment. However, it has recently been pointed out that simple chest x-rays and sputum tests conducted in health checks have poor effects on the early detection of lung cancer, and do not lead to reduction of cancer deaths. Since the number of deaths from lung cancer is considered to continuously increase, development of a novel therapeutic strategy is an urgent challenge.
On the other hand, recent developments in molecular biology and tumor immunology have elucidated that cytotoxic (killer) T cells and helper T cells recognize peptides generated by degradation of proteins that are specifically and highly expressed in cancer cells and which are presented on the surface of cancer cells or antigen presenting cells via HLA molecules, and cause an immunoreaction that destroys cancer cells. Further, many tumor antigen proteins and peptides derived therefrom, which stimulate such immunoreactions that attack these cancers, have been identified, and clinical application of antigen-specific tumor immunotherapies are now in progress.
HLA class I molecule is expressed on the surface of all nucleated cells of the body. It is expressed on the cell surface by binding to peptides generated by intracellular degradation of proteins produced in the cytoplasm or in the nucleus. On the surface of a normal cell, peptides derived from its normal proteins are bound to HLA class I molecules, and the T cells of the immune system will not identify them to destroy the cell. On the other hand, in the process of canceration, cancer cells sometimes express a large amount of proteins which are hardly or very slightly expressed in normal cells. When the HLA class I molecules bind to peptides generated by intracellular degradation of proteins specifically and highly expressed in cancer cells and then expressed on the surface of cancer cells, killer T cells will recognize them and destroy only the cancer cells. Moreover, by administering such cancer-specific antigens or peptides to an individual, an immune response that destroys cancer cells and suppresses cancer growth can be induced without harming normal cells. This is called cancer immunotherapy using cancer-specific antigens. HLA class II molecules are mainly expressed on the surface of antigen presenting cells. HLA class II molecules bind to peptides derived from cancer-specific antigens, which are generated by intracellular degradation of cancer-specific antigens incorporated into antigen presenting cells from outside of the cells, and then express on the cell surface. Helper T cells having recognized them are activated, and induce or enhance an immunoreaction against tumors by producing various cytokines which activate other immunocompetent cells.
Accordingly, if an immunotherapy that targets antigens specifically and highly expressed in these cancers is developed, such a therapy may effectively eliminate only cancers without causing any harmful event on one's own normal organs. It is also expected that the therapy can be used for any terminal cancer patients to whom other treatments should not be applied. In addition, by administering a cancer-specific antigen and peptide as a vaccine in advance to persons with a high risk of developing such cancers, cancer development may be prevented.
Although there are various therapies for pancreatic cancer, the prognosis of the cancer is very poor as compared to other cancers. This is because pancreatic cancer is difficult to detect early, progresses rapidly, and is thus often detected only at well-advanced stages. Although surgical removal is the most promising radical cure at present, respectable cases are only about 20% of the total number. Pancreas surgery is also highly invasive, and advanced cases show poor prognosis even after surgical resection. Non-removable cases are treated by chemotherapy that mainly uses gemcitabine, and radiotherapy. However, many cases show resistance to the treatment and have little cytoreductive effects, which is one of the reasons why pancreas cancer is intractable. Accordingly, if an immunotherapy targeting an antigen that is specifically and highly expressed in pancreatic cancer is developed, such a therapy may effectively eliminate only the cancer without causing any harmful events on one's own normal organs. It is also expected to become a therapy that can be applied for any patient with terminal cancer. In addition, since pancreatic cancer often recurs early after resection, the therapy is also expected to be useful as a postoperative adjunctive therapy.
The present inventors previously conducted genome-wide gene expression analysis of 27,648 human genes by cDNA microarray analysis to examine their expression profiles in 16 pancreatic cancer cases, fetal organs, and various adult normal organs. As a result, they discovered that P-cadherin (CDH3) was highly expressed in many pancreatic cancers, while it was hardly expressed in adult normal organs. Further, CDH3 was observed to be also highly expressed in most cases of cholangiocellular carcinoma, gastric cancer, colon cancer, non-small cell lung cancer, testicular cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, and the like. This fact suggests that CDH3 can be a cancer-specific antigen in many cancers.
HLA-A2 is frequently observed in human populations regardless of the race, and about 30% of the Japanese carry HLA-A2. Therefore, if a peptide presented to killer T cells by HLA-A2 can be identified, it can be widely applied to not only Japanese but also western Caucasians and the like. Accordingly, the identification of cancer antigen peptides presented to killer T cells by HLA-A2 is an important task. It may be highly beneficial to apply such cancer antigen peptides to immunotherapy for lung cancer, whose morbidity and mortality rates are high all over the world.
Prior art document information relevant to the invention of the present application is shown below.    [Non-patent Document 1] Nakamura, T., et al., Oncogene 23: 2385-2400 (2004)    [Non-patent Document 2] Obama, K., et al., Hepatology 41: 1339-1348 (2005)    [Non-patent Document 3] Taniuchi, K., et al., Cancer Res 65: 3092-3099 (2005)    [Non-patent Document 4] Soler, A. P., et al., Cancer 86: 1263-1272 (1999)    [Non-patent Document 5] Paredes, J., et al., Clin Cancer Res 11: 5869-5877 (2005)    [Non-patent Document 6] Ingunn, M., et al., J Clin Oncol 22: 1242-1252 (2004)    [Non-patent Document 7] Glenn, L., et al., J Cell Biol 139: 1025-1032 (1997)    [Non-patent Document 8] Bauer, R., et al., Exp. Mol. Pathol. 81: 224-230 (2006)    [Non-patent Document 9] Muzon-Guerra, M. F., et al. Cancer 103: 960-969 (2005)    [Non-patent Document 10] Marck, V. V., et al., Cancer Res. 65: 8774-8783 (2005)